School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
J Biol Chem. 2012 Apr 20;287(17):13840-9. doi: 10.1074/jbc.M111.317131. Epub 2012 Mar 6.
Ovarian cancer is the most lethal gynecologic malignancy in women. Despite the fact that the metastatic spread is associated with the majority of deaths from ovarian cancer, the molecular mechanisms regulating the invasive and metastatic phenotypes of ovarian cancer are poorly understood. In this study, we demonstrated that BLT2, a low affinity leukotriene B(4) receptor, is highly expressed in OVCAR-3 and SKOV-3 human ovarian cancer cells, and that this receptor plays a key role in the invasiveness and metastasis of these cells through activation of STAT3 and consequent up-regulation of matrix metalloproteinase 2 (MMP2). In addition, our results suggest that activation of NAD(P)H oxidase-4 (NOX4) and subsequent reactive oxygen species (ROS) generation lie downstream of BLT2, mediating the stimulation of STAT3-MMP2 cascade in this process. For example, knockdown of BLT2 or NOX4 using each specific siRNA suppressed STAT3 stimulation and MMP2 expression. Similarly, inhibition of STAT3 suppressed the expression of MMP2, thus leading to attenuated invasiveness of these ovarian cancer cells. Finally, the metastasis of SKOV-3 cells in nude mice was markedly suppressed by pharmacological inhibition of BLT2. Together, our results implicate a BLT2-NOX4-ROS-STAT3-MMP2 cascade in the invasiveness and metastasis of ovarian cancer cells.
卵巢癌是女性中最致命的妇科恶性肿瘤。尽管转移扩散与大多数卵巢癌死亡有关，但调节卵巢癌侵袭和转移表型的分子机制仍知之甚少。在这项研究中，我们证明了低亲和力白三烯 B4 受体 BLT2 在 OVCAR-3 和 SKOV-3 人卵巢癌细胞中高度表达，并且该受体通过激活 STAT3 并随后上调基质金属蛋白酶 2（MMP2）在这些细胞的侵袭和转移中发挥关键作用。此外，我们的结果表明，NAD(P)H 氧化酶-4（NOX4）的激活和随后的活性氧（ROS）的产生位于 BLT2 下游，介导了该过程中 STAT3-MMP2 级联的刺激。例如，使用每种特异性 siRNA 敲低 BLT2 或 NOX4 会抑制 STAT3 刺激和 MMP2 表达。同样，抑制 STAT3 会抑制 MMP2 的表达，从而导致这些卵巢癌细胞侵袭性减弱。最后，通过药理学抑制 BLT2 显著抑制了 SKOV-3 细胞在裸鼠中的转移。总之，我们的结果表明 BLT2-NOX4-ROS-STAT3-MMP2 级联在卵巢癌细胞的侵袭和转移中起作用。
